The degree of behavioral control that an organism has over a stressor is a crucial determinant of the behavioral and physiological impact of the stressor. Exposure to an uncontrollable stressor can result in numerous behavioral, neural, and immunological changes that do not occur if the identical stressor is controllable. These effects have been termed "learned helplessness effects" and include a number of features central to post-traumatic stress disorder and depression. Research has demonstrated that the neural mediation of these effects is due to the differential activation of the serotonergic (5-HT) dorsal raphe nucleus (DRN). 5-HT neurons within the DRN are activated to a greater degree following an uncontrollable stressor than to an identical, yet controllable stressor. This greater activation produces changes in 5-HT neurons that mediate the later consequences of uncontrollable stress. Yet, it is unclear which neural inputs to the DRN are critical for this differential activation. Recent evidence suggests that the medial prefrontal cortex (mPFC) is sensitive to the controllability of a stressor and differentially regulates the DRN depending on whether the stressor is controllable or not. The present proposal is designed to test a series of hypotheses related to the functional role of the mPFC in DRN regulation. The hypotheses explore a specific circuit in which a) different populations of mPFC cells are activated in response to the dimension of controllability; b) mPFC cells are able to either facilitate or inhibit DRN 5-HT activity; and c) the behavioral effects following pharmacological manipulation of different components of this circuitry.